title: Effects of the α7 nicotinic acetylcholine receptor agonist GTS-21 on the innate immune response in humans.
abstract: The vagus nerve can reflexively attenuate the innate immune response via binding of the vagal neurotransmitter acetylcholine (ACh) to the α7 nicotinic ACh receptor (α7nAChR). We recently reported potent anti-inflammatory effects of the α7nAChR agonist GTS-21 in human leukocytes. In the present work, we investigated the anti-inflammatory effects of GTS-21 on the innate immune response during experimental human endotoxemia. We performed a double-blind placebo-controlled pilot study in 14 healthy nonsmoking male volunteers. Subjects received 150 mg GTS-21 (n = 7) or placebo (n = 7) orally three times per day during 3 days before endotoxin administration and on the day of the human endotoxemia experiment. This GTS-21 dosage scheme is the highest reported to be safe in humans. Subsequently, subjects were i.v. administered 2 ng/kg endotoxin (LPS derived from Escherichia coli O:113). Serial blood withdrawals were performed to determine GTS-21 plasma concentrations and inflammatory mediators. Plasma concentrations of GTS-21 and its active metabolite 4-OH-GTS-21 were highly variable between subjects. LPS administration resulted in a transient inflammatory response. There were no differences in the LPS-induced cytokine response between the GTS-21- and placebo-treated groups. However, within the GTS-21-treated group, higher GTS-21 plasma concentrations correlated with lower levels of TNF-α (r = -0.78, P = 0.03), IL-6 (r = -0.76, P = 0.04), and IL-1RA (r = -0.86, P = 0.01), but not IL-10 (r = -0.35, P = 0.25). In conclusion, although higher GTS-21 plasma concentrations significantly correlated with lower cytokine levels, the highest dose tested to be safe in humans did not result in significant differences in inflammatory mediators between the GTS-21- and placebo-treated groups.
authors.affiliation: Department of Intensive Care Medicine, Radboud University Nijmegen Medical Centre, Internal Mail 685, Geert Grooteplein 10, 6500 HB, Nijmegen, The Netherlands. m.kox@ic.umcn.nl
authors.forename: Matthijs
authors.initials: M
authors.lastname: Kox
authors.forename: Jan C
authors.initials: JC
authors.lastname: Pompe
authors.forename: Marije C
authors.initials: MC
authors.lastname: Gordinou de Gouberville
authors.forename: Johannes G
authors.initials: JG
authors.lastname: van der Hoeven
authors.forename: Cornelia W
authors.initials: CW
authors.lastname: Hoedemaekers
authors.forename: Peter
authors.initials: P
authors.lastname: Pickkers
mesh_terms: D000293:Adolescent; D000328:Adult; D000893:Anti-Inflammatory Agents / Q000097:blood / Q000494:pharmacology*; D001597:Benzylidene Compounds / Q000097:blood / Q000494:pharmacology*; D019446:Endotoxemia / Q000097:blood* / Q000139:chemically induced / Q000276:immunology*; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000097:blood; D016753:Interleukin-10 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D018722:Nicotinic Agonists / Q000097:blood / Q000494:pharmacology*; D011725:Pyridines / Q000097:blood / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D055815:Young Adult; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D000893:Anti-Inflammatory Agents; D001597:Benzylidene Compounds; C579167:Chrna7 protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D015850:Interleukin-6; D008070:Lipopolysaccharides; D018722:Nicotinic Agonists; D011725:Pyridines; D011978:Receptors, Nicotinic; D014409:Tumor Necrosis Factor-alpha; D064569:alpha7 Nicotinic Acetylcholine Receptor; D016753:Interleukin-10; C088936:3-(2,4-dimethoxybenzylidene)anabaseine